Substituted isoxazoline derivatives

Abstract

This invention recites substituted isoxazoline derivatives of Formula (1) or a veterinarily acceptable salt thereof, with parasiticidal activity, compositions thereof, and their use as a parasiticide in animals or birds where R 1a , R 1b , R 1c , R 2 , R 3 , and n are as described herein.

1 . A compound of Formula (1) 
       
         
           
           
               
               
           
         
       
       or a veterinarily acceptable salt thereof, wherein
 R 1a , R 1b , and R 1c  are each independently selected from halogen, cyano, C 1 -C 8  alkyl, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy, and each R 1  may be identical with or different from each other; 
 R 2  is hydrogen, halo, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 3 -C 6  cycloalkyl, where n is an integer 1, 2, or 3, and when n is 2 or 3, each R 2  may be identical with or different from each other; 
 R 3  is selected from C 1 -C 8  alkyl, C 0 -C 3  alkylC 3 -C 6  cycloalkyl, C 1 -C 6  alkyl-OR 4 , or C 1 -C 6  alkylC(O)NR a R b , wherein the C 1 -C 8  alkyl and the C 0 -C 3  alkylC 3 -C 6  cycloalkyl are optionally substituted with at least one substituent selected from halo, cyano, hydroxyl, and S(O) p R 4 ; 
 R 4  is C 1 -C 6  alkyl or C 1 -C 6  haloalkyl; 
 R a  is hydrogen or C 1 -C 6  alkyl; 
 R b  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 0 -C 4 alkylC 3 -C 6 cycloalkyl, or C 1 -C 3 alkylHet, wherein Het is a 5- or 6-membered monocyclic aromatic ring containing at least one heteroatom selected from N, O, or S, and the Het can be optionally substituted with at least one substituent selected from halo, cyano, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; and 
 
       p is the integer 0, 1, or 2. 
     
     
         2 . The compound of  claim 1  wherein
 R 1a , R 1b , and R 1c  are each independently selected from halogen, cyano, C 1 -C 8  alkyl, and C 1 -C 6  haloalkyl, or one of R 1a , R 1b  or R 1c  is SO 2 CF 3 . 
 
     
     
         3 . The compound of  claim 2  having Formula (1A), (1B), (1C), or (1D) 
       
         
           
           
               
               
           
         
       
       or a veterinarily acceptable salt thereof, wherein
 R 1a , R 1b , and R 1c  are each independently selected from halogen, cyano, C 1 -C 8  alkyl, and C 1 -C 6  haloalkyl, or one of R 1a , R 1b , or R 1c  is SO 2 CF 3 , and 
 R 2a , R 2b , and R 2c  are each independently hydrogen, halo, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 3 -C 6 cycloalkyl. 
 
     
     
         4 . The compound of  claim 3  having Formula (1D) 
       
         
           
           
               
               
           
         
       
       or a veterinarily acceptable salt thereof, wherein
 R 1a , R 1b , and R 1c  are each independently selected from halogen, cyano, C 1 -C 8 alkyl, and C 1 -C 6  haloalkyl, or one of R 1a , R 1b , or R 1c  is —SO 2 CF 3 ; and 
 R 2c  is hydrogen, halo, cyano, methyl, ethyl, —CF 3 , —CH 2 CF 3 , cyclopropyl or cyclobutyl. 
 
     
     
         5 . The compound of  claim 4  wherein
 R 1a , R 1b , and R 1c  are each independently selected from fluoro, chloro, bromo, cyano, methyl, ethyl, —CF 3 , and —CH 2 CF 3 ; and 
 R 2c  is hydrogen, fluoro, chloro, bromo, cyano, methyl, or CF 3 . 
 
     
     
         6 . The compound of  claim 5  wherein R 1a , R 1b , and R 1c  are each independently selected from fluoro, chloro, bromo, and CF 3 ; and
 R 2c  is fluoro, chloro, bromo, methyl, or CF 3 . 
 
     
     
         7 . The compound of  claim 6  wherein
 R 3  is selected from C 1 -C 8  alkyl or C 0 -C 3  alkylC 3 -C 6  cycloalkyl; wherein the C 1 -C 8  alkyl and the C 0 -C 3  alkylC 3 -C 6  cycloalkyl are optionally substituted with at least one substituent selected from halo, hydroxyl, and S(O) p R 4  where p is the integer 0, 1, or 2, and R 4  is methyl, ethyl, or isopropyl. 
 
     
     
         8 . The compound of  claim 7  wherein
 R 3  is selected from C 1 -C 8  alkyl, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, ethylcyclobutyl, and methyl cyclopentyl; wherein the C 1 -C 8  alkyl and the cycloalkyl or alkyl cycloalkyl are optionally substituted with at least one substituent selected from halo, hydroxyl, —SCH 3 , and —S(O) 2 CH 3 . 
 
     
     
         9 . A compound of  claim 1  selected from
 N-{5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamide; 
 N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanamide; 
 N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarboxamide; 
 N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclobutanecarboxamide; 
 N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}propanamide; 
 2-cyclopropyl-N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamide; 
 N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-3-methylbutanamide; 
 2-cyclopropyl-N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamide; 
 N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamide; 
 N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}cyclopropanecarboxamide; 
 N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}-3,3-difluorocyclobutanecarboxamide 
 N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamide; 
 N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarboxamide; 
 N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanamide; 
 N-{2-chloro-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamide; 
 N-(2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzyl)acetamide; 
 N-Cyclopropylmethyl-N′-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzyl}-malonamide; and 
 N-ethyl-N′-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]benzyl}malonamide; 
 or a veterinarily acceptable salt thereof. 
 
     
     
         10 . A veterinary composition comprising a therapeutically effective amount of a compound of Formula (1) 
       
         
           
           
               
               
           
         
       
       or a veterinarily acceptable salt thereof, wherein
 R 1a , R 1b , and R 1c  are each independently selected from halogen, cyano, C 1 -C 8  alkyl, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy, and each R 1  may be identical with or different from each other; 
 R 2  is hydrogen, halo, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 3 -C 6 cycloalkyl, where n is an integer 1, 2, or 3, and when n is 2 or 3, each R 2  may be identical with or different from each other; 
 R 3  is selected from C 1 -C 8  alkyl, C 0 -C 3  alkylC 3 -C 6  cycloalkyl, C 1 -C 6  alkyl-OR 4 , or C 1 -C 6  alkylC(O)NR a R b , wherein the C 1 -C 8  alkyl and the C 0 -C 3  alkylC 3 -C 6  cycloalkyl are optionally substituted with at least one substituent selected from halo, cyano, hydroxyl, and S(O) p R 4 ; 
 R 4  is C 1 -C 6  alkyl or C 1 -C 6  haloalkyl; 
 R a  is hydrogen or C 1 -C 6  alkyl; 
 R b  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 0 -C 4 alkylC 3 -C 6 cycloalkyl, or C 1 -C 3 alkylHet, wherein Het is a 5- or 6-membered monocyclic aromatic ring containing at least one heteroatom selected from N, O, or S, and the Het can be optionally substituted with at least one substituent selected from halo, cyano, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; and 
 
       p is the integer 0, 1, or 2. 
     
     
         11 . The veterinary composition of  claim 10  further comprising a veterinarily acceptable excipient, diluent, or carrier. 
     
     
         12 . The veterinary composition of  claim 11  further comprising at least one additional veterinary agent. 
     
     
         13 . A method for the treatment of parasites in an animal or bird comprising administering to said animal or bird an effective amount of a compound of Formula (1) 
       
         
           
           
               
               
           
         
       
       or a veterinarily acceptable salt thereof, wherein
 R 1a , R 1b , and R 1b  are each independently selected from halogen, cyano, C 1 -C 8  alkyl, C 1 -C 6  haloalkyl, and C 1 -C 6  haloalkoxy, and each R 1  may be identical with or different from each other; 
 R 2  is hydrogen, halo, cyano, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, or C 1 -C 6  alkoxy, C 1 -C 6  haloalkoxy, C 3 -C 6 cycloalkyl, where n is an integer 1, 2, or 3, and when n is 2 or 3, each R 2  may be identical with or different from each other; 
 R 3  is selected from C 1 -C 8  alkyl, C 0 -C 3  alkylC 3 -C 6  cycloalkyl, C 1 -C 6  alkyl-OR 4 , or C 1 -C 6  alkylC(O)NR a R b , wherein the C 1 -C 8  alkyl and the C 0 -C 3  alkylC 3 -C 6  cycloalkyl are optionally substituted with at least one substituent selected from halo, cyano, hydroxyl, and S(O) p R 4 ; 
 R 4  is C 1 -C 6  alkyl or C 1 -C 6  haloalkyl; 
 R a  is hydrogen or C 1 -C 6  alkyl; 
 R b  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 0 -C 4 alkylC 3 -C 6 cycloalkyl, or C 1 -C 3 alkylHet, wherein Het is a 5- or 6-membered monocyclic aromatic ring containing at least one heteroatom selected from N, O, or S, and the Het can be optionally substituted with at least one substituent selected from halo, cyano, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl; and 
 
       p is the integer 0, 1, or 2. 
     
     
         14 . The method of  claim 13  wherein the compound is administered orally or topically and the animal is a companion animal or livestock and the bird is fowl. 
     
     
         15 . The method of  claim 14  wherein the companion animal is dog, cat, and horse, and livestock is bovine and ovine.